As an organism grows, its sensation also changes. At first, an embryo takes on an almost fluid state which allows its cells to divide and develop. As it matures, its tissues and organs harden into their final shape. In some species, this physical state of an organism can be an indicator of its stage of development, or even of the general state of its health.
Today, researchers at MIT have discovered that the way cells in a tissue are arranged can serve as a fingerprint for the âphaseâ of the tissue. They developed a method to decode images of cells in tissue to quickly determine whether that tissue looks more like a solid, a liquid, or even a gas. Their findings are published this week in the Proceedings of the National Academy of Sciences.
The team hopes their method, which they dubbed ‘configurational fingerprints’, can help scientists track physical changes in an embryo as it develops. More immediately, they apply their method to study and possibly diagnose a specific type of tissue: tumors.
In the case of cancer, evidence suggests that, like an embryo, the physical state of a tumor may indicate its stage of growth. Stronger tumors can be relatively stable, while more fluid growths might be more prone to mutate and metastasize.
MIT researchers are analyzing images of tumors, both grown in the lab and biopsied from patients, to identify cell fingerprints that indicate whether a tumor looks more like a solid, liquid, or gas. They envision that doctors could one day match a picture of tumor cells with a cell fingerprint to quickly determine the phase of a tumor and ultimately the progression of cancer.
“Our method would allow very easy diagnosis of cancerous conditions, simply by examining the positions of cells in a biopsy,” says Ming Guo, associate professor of mechanical engineering at MIT. “We hope that by just looking at where the cells are, doctors can tell directly if a tumor is very solid, which means it cannot yet metastasize, or if it is more fluid and a patient is in danger.”
Guo’s co-authors are Haiqian Yang, Yulong Han, Wenhui Tang and Rohan Abeyaratne from MIT, Adrian Pegoraro from the University of Ottawa, and Dapeng Bi from Northeastern University.
In a perfect solid, the individual constituents of the material are configured as an ordered lattice, like the atoms in a crystal cube. If you were to cut a slice of the crystal and lay it on a table, you would see that the atoms are arranged in such a way that you can connect them in a pattern of repeated triangles. In a perfect solid, since the spacing between atoms would be exactly the same, the triangles connecting them would generally be equilateral in shape.
Guo took this construct as a template for a perfectly solid structure, with the idea that it could serve as a benchmark for comparing the cellular configurations of actual, less than perfectly solid tissues and tumors.
âReal fabrics are never perfectly ordered,â Guo says. âThey are mostly messy. But still, there are subtle differences in how messy they are.
Following this idea, the team started with images of various types of tissue and used software to map the triangular connections between cells in a tissue. Unlike equilateral triangles in a perfect solid, the maps produced triangles of different shapes and sizes, indicating cells with a range of spatial order (and disorder).
For each triangle in an image, they measured two key parameters: volumetric order, or the space within a triangle; and the shear order, or the distance between the shape of a triangle and the equilateral. The first parameter indicates the fluctuation in the density of a material, while the second illustrates the tendency of the material to deform. These two parameters, they found, were sufficient to determine whether a tissue looked more like a solid, a liquid, or a gas.
âWe directly calculate the exact value of the two parameters, compared to those of a perfect solid, and use those exact values ââas our fingerprints,â Guo explains.
The team tested their new fingerprinting technique in several different scenarios. The first was a simulation in which they modeled the mixture of two types of molecules, the concentration of which they gradually increased. For each concentration, they mapped the molecules into triangles, then measured the two parameters of each triangle. From these measurements, they characterized the phase of the molecules and were able to reproduce the transitions between gas, liquid and solid, which were expected.
âPeople know what to expect in this very simple system, and that’s exactly what we’re seeing,â Guo explains. âIt demonstrated the capacity of our method. “
The researchers then applied their method in systems with cells rather than molecules. For example, they watched videos, taken by other researchers, of a growing fruit fly wing. By applying their method, they were able to identify regions of the developing wing that went from a solid state to a more fluid state.
âAs a fluid, it can help with growth,â Guo explains. âHow exactly this happens is still under investigation. “
He and his team also developed small tumors from cells in human breast tissue and observed that the tumors developed into tendrils resembling appendages – signs of early metastasis. When they mapped the configuration of cells in tumors, they found that non-invasive tumors looked something between a solid and a liquid, and invasive tumors looked more like gas, while the tendrils showed a state even more messy.
âThe invasive tumors looked more like steam, and they want to spread and go everywhere,â Guo explains. âLiquids can hardly be compressed. But gases are compressible – they can swell and shrink easily, and that’s what we see here.
The team works with human cancer biopsy samples, which they image and analyze to refine their cellular fingerprints. Ultimately, Guo envisions that mapping the phases of a tissue can be a quick and less invasive way to diagnose several types of cancer.
âDoctors usually have to take biopsies and then stain different markers depending on the type of cancer, to diagnose,â Guo explains. “Maybe one day we can use optical tools to look inside the body, without touching the patient, to see the position of the cells and tell directly what stage of cancer a patient is in.”
This research was funded in part by the National Institutes of Health, MathWorks and the Jeptha H. and Emily V. Wade Prize at MIT.